Study summary · research use only
FOXO transcription factors as mediators of stress adaptation
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This review, species not specified beyond referencing C. elegans research, discusses the FOXO family of transcription factors (FOXO1, FOXO3, FOXO4, FOXO6) as mammalian orthologues of the C. elegans DAF-16 protein, noted for its capacity to double lifespan in the absence of daf-2, the worm insulin receptor gene. It summarizes findings on FOXO regulation and activity and how conditional knockout studies show FOXOs control development and homeostasis at organ and organism levels. The authors describe DAF-16/FOXO's lifespan-extending capability as correlated with induction of stress response pathways, and note that decreased FOXO activity is linked to age-related diseases such as cancer and diabetes, while the same FOXO-mediated responses can also help dysfunctional cells survive once they emerge.
Abstract
The forkhead box protein O (FOXO, consisting of FOXO1, FOXO3, FOXO4 and FOXO6) transcription factors are the mammalian orthologues of Caenorhabditis elegans DAF-16, which gained notoriety for its capability to double lifespan in the absence of daf-2 (the gene encoding the worm insulin receptor homologue). Since then, research has provided many mechanistic details on FOXO regulation and FOXO activity. Furthermore, conditional knockout experiments have provided a wealth of data as to how FOXOs control development and homeostasis at the organ and organism levels. The lifespan-extending capabilities of DAF-16/FOXO are highly correlated with their ability to induce stress response pathways. Exogenous and endogenous stress, such as cellular redox stress, are considered the main drivers of the functional decline that characterizes ageing. Functional decline often manifests as disease, and decrease in FOXO activity indeed negatively impacts on major age-related diseases such as cancer and diabetes. In this context, the main function of FOXOs is considered to preserve cellular and organismal homeostasis, through regulation of stress response pathways. Paradoxically, the same FOXO-mediated responses can also aid the survival of dysfunctional cells once these eventually emerge. This general property to control stress responses may underlie the complex and less-evident roles of FOXOs in human lifespan as opposed to model organisms such as C. elegans.
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